Aging in mammals or other animals can have profound negative effects on the cognitive and motor functions of the subject. Genes that regulate the aging pathways and genes that could slow, pause, or decrease the effects of aging and/or increase lifespan are of great interest, because of their potential to increase longevity or enhance quality of life during the later part of the subject's lifespan.
Studies in model organisms have shown that the aging process is regulated by conserved mechanisms. For example, lifespan extension has been achieved in multiple animal systems by inactivation of the insulin-like receptor signal transduction pathway (Kenyon (2001) “A conserved regulatory system for aging” Cell 105:165-8). Reduction of mitochondrial function has also been shown to increase lifespan. For example, mutations in the iron sulfur component of complex III, isp-1, increase longevity by decreasing oxygen consumption (Dillin et al. (2002) Science 298:2398-401, Feng et al. (2001) Dev Cell 1:633-644, and Lee et al. (2003) Nat. Genet. 33:40-48).
In addition, reduced food intake as a result of dietary restriction increases the lifespan of a wide variety of metazoans and delays the onset of multiple age-related pathologies. This is a conserved phenomenon in a number of species, e.g., yeast, worms, flies, mice, waterstriders, guppies, chickens, labradors, and rats. Dietary restriction elicits a genetically programmed response to nutrient availability that cannot be explained by a simple reduction in metabolism or slower growth of the organism.
However, although considerable progress has been made in understanding aging, there is still need for elucidation of the pathways that influence aging, as well as for novel ways to increase longevity and decrease the effects of aging.
Among other benefits, the present invention meets the above needs by providing the identity of a key pathway that mediates dietary restriction-induced longevity (the ubiquitin pathway), by providing methods for screening for modulators of aging and longevity, and by providing methods for regulating longevity. A complete understanding of the invention will be obtained upon review of the following.